Onset Of Response Research Articles

Brg1 Supports B Cell Proliferation and Germinal Center Formation Through Enhancer Activation.

Activation and differentiation of B cells depend on extensive rewiring of gene expression networks through changes in chromatin structure and accessibility. The chromatin remodeling complex BAF with its catalytic subunit Brg1 was previously identified as an essential regulator of early B cell development, however, how Brg1 orchestrates gene expression during mature B cell activation is less clear. Here, we find that Brg1 is required for B cell proliferation and germinal center formation through selective interactions with enhancers. Brg1 recruitment to enhancers following B cell activation was associated with increased chromatin accessibility and transcriptional activation of their coupled promoters, thereby regulating the expression of cell cycle-associated genes. Accordingly, Brg1-deficient B cells were unable to mount germinal center reactions and support the formation of class-switched plasma cells. Our findings show that changes in B cell transcriptomes that support B cell proliferation and GC formation depend on enhancer activation by Brg1. Thus, the BAF complex plays a critical role during the onset of the humoral immune response.

Bimekizumab: a dual IL-17A and IL-17F inhibitor for the treatment of psoriasis and psoriatic arthritis

ABSTRACT Introduction Interleukin (IL)-17 is critical in the pathogenesis of psoriasis and psoriatic arthritis (PsA) with most data suggesting that IL-17A alone was the key cytokine. However, in vitro and in vivo studies have suggested dual blockade of IL-17A and IL-17 F may be more effective than IL-17 A blockade alone. Bimekizumab is the first human monoclonal antibody to exert simultaneous specific inhibition of IL-17A and IL-17 F, and has been studied in several phase II/III trials for psoriasis and PsA. Areas covered Bimekizumab is not currently licensed for use. A literature search identified clinical trials examining the efficacy and safety of bimekizumab for psoriasis and PsA, and these were critically appraised. Expert opinion Clinical trials of bimekizumab have been promising, demonstrating a rapid onset of response and superior efficacy compared to three currently licensed biologics: secukinumab, ustekinumab, and adalimumab. Bimekizumab maintains a high level of efficacy with maintenance dosing intervals of 8 weeks, compared with 4 weeks for currently licensed IL-17A antagonists. No unexpected adverse events have been identified, although mild-to-moderate fungal infections occur in approximately 10%. Studies over longer time periods involving additional active comparators would be valuable in further defining the role of bimekizumab amongst currently available treatments.

From the Editor’s Desk…

From the Editor’s Desk…

Timing and durability of response to erenumab in patients with chronic migraine.

BackgroundErenumab is a human anti‐calcitonin gene‐related peptide receptor monoclonal antibody approved for migraine prevention. We sought to further assess the temporal patterns of response to erenumab in patients with chronic migraine (CM), specifically the onset and sustainability of monthly migraine day (MMD) response.MethodsThis is a post hoc analysis of a 12‐week, randomized, double‐blind, placebo‐controlled study of erenumab for migraine prevention in patients with CM (≥15 headache days/month, including ≥8 migraine days/month). Onset and sustainability were assessed according to MMD reduction from baseline, with the following response categories: responders (≥50% reduction), partial responders (≥30% and <50%), or nonresponders (<30%).ResultsAmong the erenumab 140 mg group (n = 187), 54.0% (101/187) achieved a response at any month during the study with a median time to onset of monthly response of 1 month. This improvement was maintained in most patients with continued treatment. An initial response was achieved at Month 1 by 28.3% (53/187) of patients; 69.8% (37/53) of whom maintained a response at Months 2 and 3. Although many patients responded early, some patients required longer treatment to achieve a response; 79.4% (27/34) of initial partial responders and 21.0% (21/100) of initial nonresponders subsequently achieved a response. Similar findings were observed for the erenumab 70mg group (n = 188).ConclusionA majority of erenumab‐treated patients with CM who achieved an initial response at Month 1 sustained this benefit. Many patients responded later with continued treatment. Our data support recommendations to assess outcomes after ≥3 months of preventive treatment with erenumab in CM.

Diversity of neurovascular coupling dynamics along vascular arbors in layer II/III somatosensory cortex

The spatial-temporal sequence of cerebral blood flow (CBF), cerebral blood volume (CBV) and blood velocity changes triggered by neuronal activation is critical for understanding functional brain imaging. This sequence follows a stereotypic pattern of changes across different zones of the vasculature in the olfactory bulb, the first relay of olfaction. However, in the cerebral cortex, where most human brain mapping studies are performed, the timing of activity evoked vascular events remains controversial. Here we utilized a single whisker stimulation model to map out functional hyperemia along vascular arbours from layer II/III to the surface of primary somatosensory cortex, in anesthetized and awake Thy1-GCaMP6 mice. We demonstrate that sensory stimulation triggers an increase in blood velocity within the mid-capillary bed and a dilation of upstream large capillaries, and the penetrating and pial arterioles. We report that under physiological stimulation, response onset times are highly variable across compartments of different vascular arbours. Furthermore, generating transfer functions (TFs) between neuronal Ca2+ and vascular dynamics across different brain states demonstrates that anesthesia decelerates neurovascular coupling (NVC). This spatial-temporal pattern of vascular events demonstrates functional diversity not only between different brain regions but also at the level of different vascular arbours within supragranular layers of the cerebral cortex.

A Reversible Low Frequency Alternating Current Nerve Conduction Block Applied to Mammalian Autonomic Nerves.

Electrical stimulation can be used to modulate activity within the nervous system in one of two modes: (1) Activation, where activity is added to the neural signalling pathways, or (2) Block, where activity in the nerve is reduced or eliminated. In principle, electrical nerve conduction block has many attractive properties compared to pharmaceutical or surgical interventions. These include reversibility, localization, and tunability for nerve caliber and type. However, methods to effect electrical nerve block are relatively new. Some methods can have associated drawbacks, such as the need for large currents, the production of irreversible chemical byproducts, and onset responses. These can lead to irreversible nerve damage or undesirable neural responses. In the present study we describe a novel low frequency alternating current blocking waveform (LFACb) and measure its efficacy to reversibly block the bradycardic effect elicited by vagal stimulation in anaesthetised rat model. The waveform is a sinusoidal, zero mean(charge balanced), current waveform presented at 1 Hz to bipolar electrodes. Standard pulse stimulation was delivered through Pt-Black coated PtIr bipolar hook electrodes to evoke bradycardia. The conditioning LFAC waveform was presented either through a set of CorTec® bipolar cuff electrodes with Amplicoat® coated Pt contacts, or a second set of Pt Black coated PtIr hook electrodes. The conditioning electrodes were placed caudal to the pulse stimulation hook electrodes. Block of bradycardic effect was assessed by quantifying changes in heart rate during the stimulation stages of LFAC alone, LFAC-and-vagal, and vagal alone. The LFAC achieved and block using hook (N = 7) and cuff (N = 5) electrodes, respectively, at current levels less than 110 µAp (current to peak). The potential across the LFAC delivering electrodes were continuously monitored to verify that the blocking effect was immediately reversed upon discontinuing the LFAC. Thus, LFACb produced a high degree of nerve block at current levels comparable to pulse stimulation amplitudes to activate nerves, resulting in a measurable functional change of a biomarker in the mammalian nervous system.

Abstract CT252: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ruxolitinib Plus Parsaclisib in Patients with JAK- and PI3K-Inhibitor Treatment-Naïve Myelofibrosis

Abstract Background: Ruxolitinib (JAK1/JAK2 inhibitor) significantly improves outcomes in patients with myelofibrosis (MF); however, a subset of patients may experience a suboptimal response. Recent phase 2 data showed that addition of PI3Kδ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub. EHA2020. S216). This phase 3, randomized, double-blind study (INCB 50465-313; NCT04551066), evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naïve to Janus kinase (JAK) and PI3K inhibitor therapies. Methods: Eligible patients are aged ≥18 years with a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) risk category of at least Intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin, total symptom score ≥10 at screening, ECOG PS 0-2, and life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF within 3 months of first study dose and/or lack of recovery from all toxicities related to previous therapies to grade ≤1, have recent history of inadequate bone marrow reserve (eg, platelet count &amp;lt;50×109/L) or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg QD or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×109/L vs 50 to &amp;lt;100×109/L inclusive). Treatment will begin on Day 1, with starting ruxolitinib dose level determined by baseline platelet count, and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to crossover to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at Week 24 for patients who received ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability for ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Sites are opening across the US, Canada, EU, and Asia. Citation Format: Abdulraheem Yacoub, Sue Erickson-Viitanen, Feng Zhou, Albert Assad. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ruxolitinib Plus Parsaclisib in Patients with JAK- and PI3K-Inhibitor Treatment-Naïve Myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT252.

Abstract CT253: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Parsaclisib Plus Ruxolitinib in Patients with Myelofibrosis Who Have Suboptimal Response to Ruxolitinib

Abstract Background: Ruxolitinib (JAK1/JAK2 inhibitor) is indicated for the treatment of adults with intermediate (INT) or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF, but a subset of patients may exhibit a suboptimal response due to possible persistent PI3K/AKT activation. Targeting PI3K/AKT signaling may therefore have clinically relevant effects on MF disease burden. This phase 3, randomized, double-blind, placebo-controlled study will determine the effect of add-on parsaclisib, a highly selective PI3Kδ inhibitor, on signs and symptoms of MF in patients with suboptimal or declining response to stable ruxolitinib treatment (INCB 50465-304; NCT04551053). Methods: Eligible patients are aged ≥18 years with a diagnosis of at least INT-1-risk category according to the Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF, have received ruxolitinib for ≥3 months with a stable dose (5-25 mg twice daily) for ≥8 weeks prior to receiving the first dose of study drug (Day 1), have evidence of suboptimal response to ruxolitinib (palpable spleen ≥5 cm below left subcostal margin, and total symptom score ≥10), and ECOG PS ≤2. Patients are excluded if they received prior therapy with any PI3K inhibitor, experimental or standard drug therapy for MF (except ruxolitinib) within 3 months of starting study drug, or have platelet count &amp;lt;50×109/L, recent history of inadequate bone marrow reserve, or inadequate liver or renal function at screening. Approximately 212 patients on a stable dose of ruxolitinib will be randomized (1:1) to receive add-on parsaclisib 5 mg daily or matching placebo beginning on Day 1, with stratification by platelet count (≥100×109/L or 50 to &amp;lt;100×109/L) and DIPSS risk category (high, INT-2, or INT-1) at randomization. Treatment will continue as long as tolerated and discontinuation criteria are not met. Upon patient completion of 24 weeks of treatment, he/she will be unblinded and if randomized to ruxolitinib plus placebo and with adequate hematology parameters, the patient will be able to crossover to receive ruxolitinib plus add-on parsaclisib. The primary objective is to evaluate and compare the efficacy of add-on parsaclisib versus placebo on spleen volume at Week 24. Secondary objectives are to evaluate and compare the effect of add-on parsaclisib versus placebo on: patient-reported MF symptoms, overall survival, time to onset and duration of spleen volume response, and safety and tolerability. Sites are opening throughout the US, EU, China and Japan. Citation Format: Abdulraheem Yacoub, Michael Stouffs, Feng Zhou, Albert Assad. A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Parsaclisib Plus Ruxolitinib in Patients with Myelofibrosis Who Have Suboptimal Response to Ruxolitinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT253.

Watching the Brain as It (Un)Binds: Beta Synchronization Relates to Distractor-Response Binding.

Human action control relies on event files, that is, short-term stimulus-response bindings that result from the integration of perception and action. The present EEG study examined oscillatory brain activities related to the integration and disintegration of event files in the distractor-response binding (DRB) task, which relies on a sequential prime-probe structure with orthogonal variation of distractor and response relations between prime and probe. Behavioral results indicated a DRB effect in RTs, which was moderated by the duration of the response-stimulus interval (RSI) between prime response and probe stimulus onset. Indeed, a DRB effect was observed for a short RSI of 500 msec but not for a longer RSI of 2000 msec, indicating disintegration of event files over time. EEG results revealed a positive correlation between individual DRB in the RSI-2000 condition and postmovement beta synchronization after both prime and probe responses. Beamformer analysis localized this correlation effect to the middle occipital gyrus, which also showed highest coherency with precentral and inferior parietal brain regions. Together, these findings suggest that postmovement beta synchronization is a marker of event file disintegration, with the left middle occipital gyrus being a hub region for stimulus-response bindings in the visual DRB task.

Mechanisms of lactic acid gustatory attraction in Drosophila

Sour has been studied almost exclusively as an aversive taste modality. Yet recent work in Drosophila demonstrates that specific carboxylic acids are attractive at ecologically relevant concentrations. Here, we demonstrate that lactic acid is an appetitive and energetic tastant, which stimulates feeding through activation of sweet gustatory receptor neurons (GRNs). This activation displays distinct, mechanistically separable stimulus onset and removal phases. Ionotropic receptor 25a (IR25a) primarily mediates the onset response, which shows specificity for the lactate anion and drives feeding initiation through proboscis extension. Conversely, sweet gustatory receptors (Gr64a-f) mediate a non-specific removal response to low pH that primarily impacts ingestion. While mutations in either receptor family have marginal impacts on feeding, lactic acid attraction is completely abolished in combined mutants. Thus, specific components of lactic acid are detected through two classes of receptors to activate a single set of sensory neurons in physiologically distinct ways, ultimately leading to robust behavioral attraction.

Lepromatous leprosy mimicking systemic lupus erythematosus

We describe a case of a 36-year-old woman who presented with bilateral symmetrical polyarthritis of the hands, malar rash, and discoid rash over three months. She was initially diagnosed and treated as systemic lupus erythematosus but later proven to have lepromatous leprosy. The patient showed a remarkable improvement after the administration of steroids. Due to typical features of a connectivetissue disorder, a positive serological marker, photosensitivity, typical age of onset and initial response to treatment led to the confusion and delay in diagnosis of lepromatous leprosy. Further, this case emphasizes the importance of obtaining a detailed contact history and taking a skin biopsy even in a typical connective tissue lesion. Our case illustrates an unusual presentation of lepromatous leprosy mimicking systemic lupus erythematosus.

Comparison of the Clinical and Treatment Characteristics of Patients Undergoing Electroconvulsive Therapy for Catatonia Indication in the Context of Gender.

The aim of this study was to compare in the context of gender both clinical diagnosis and disease-related differences and electroconvulsive therapy (ECT)-related differences in data and efficacy in hospitalized patients with catatonic signs and symptoms. Data from 106 patients who received ECT with catatonia indication were retrospectively analyzed. Clinical data of male (n = 58) and female (n = 48) patients were compared. Hospitalization documents and outpatient files, sociodemographic and clinical data form, Clinical Global Improvement scores used by the ECT unit in the follow-up of patients who received ECT were used in the study. It was seen that the mean age of women at the onset of ECT was higher than in men and the presence of prolonged seizures was more common than men. In men, it was found out that the average number of sessions with the onset of clinical response to treatment was higher than the average of women. The distribution of diagnoses by gender showed that the presence of schizophrenia diagnosis in men and of bipolar disorder in women were significantly more frequent compared to the opposite sex. It was found out that there were no significant differences between genders in terms of response rate to ECT. Our study is important for being the first study in the literature investigating the gender differences in ECT used for catatonia. However, gender is not a distinctive factor in the effectiveness of treatment, there are some important differences between male and female patients showing signs and symptoms of catatonia and undergoing ECT.

The dynamics of early empathy in children: changes according to age and mothers emotional state / A dinâmica da empatia precoce nas crianças: mudanças de acordo com a idade e o estado emocional das mães

Empathy in children is an important process that allows social interaction, but little is known about its onset, dynamics, development as well as the influence of the mother´s affective state. In this study, we aimed 1) to compare the dynamics of empathic responses of two groups of healthy children (11-12 and 14-15 months) in a well-established model of simulated distress by the mother and 2) to assess the association between children's empathic responses and mother's anxiety, depressive symptomatology and empathy trait. We show that children exhibited the full repertoire of empathic components from 11-12 months.. The dynamic profile of the affective and cognitive empathic responses in the pain and recovery phases changed according to the age of the children. In addition, we found that maternal anxiety was correlated with children ?s affective responses in an opposite manner according to children´s age while maternal empathy was only correlated with affective behaviors in younger children. In conclusion, this study underscores the early onset of empathic responses as well as their dynamic character. A distinct profile of responses emerged according to children's age, emphasizing the necessity to analyze the timing of the empathic responses during development. This study also stresses mother´s affective state and empathy as important modulators of children´s empathy.

Tomato Graft Union Failure Is Associated with Alterations in Tissue Development and the Onset of Cell Wall Defense Responses

Grafting is a technique applied to a considerable number of crops, with tomato standing out. However, this technique is limited by the obtaining of unfunctional grafts, which decrease the success rate and therefore the benefits achieved. The aim of this work was to analyze the failure in intraspecific grafting of tomato plants, focusing on tissue development, cell wall defense reactions, and the distribution of starch and soluble sugars at the graft junction. The success rate in autografts was higher than that of homografts and heterografts. Unfunctional homografts and heterografts showed similar responses: absence of vascular reconnections and lack of adhesion between scion and rootstock, even though callus cell clusters and differentiation of new vasculature were produced. The scions of unfunctional grafts accumulated more starch and soluble sugars than the rootstocks, showing a strong asymmetry in the response. In addition, three types of deposits were observed in the cell walls of unfunctional grafts: lignin, suberin, and callose, with the combined accumulation of more than one of them being frequent, particularly lignin and suberin. These deposits apparently prevent adhesion and seem to be a major cause of graft failure.

A phenomenological spiking model for octopus cells in the posterior\u2013ventral cochlear nucleus

Octopus cells in the posteroventral cochlear nucleus exhibit characteristic onset responses to broad band transients but are little investigated in response to more complex sound stimuli. In this paper, we propose a phenomenological, but biophysically motivated, modeling approach that allows to simulate responses of large populations of octopus cells to arbitrary sound pressure waves. The model depends on only few parameters and reproduces basic physiological characteristics like onset firing and phase locking to amplitude modulations. Simulated responses to speech stimuli suggest that octopus cells are particularly sensitive to high-frequency transients in natural sounds and their sustained firing to phonemes provides a population code for sound level.

The Onset-Offset N1-P2 Auditory Evoked Response in Individuals With High-Frequency Sensorineural Hearing Loss: Responses to Broadband Noise.

Purpose Clinical use of electrophysiologic measures has been limited to use of brief stimuli to evoke responses. While brief stimuli elicit onset responses in individuals with normal hearing and normal central auditory nervous system (CANS) function, responses represent the integrity of a fraction of the mainly excitatory central auditory neurons. Longer stimuli could provide information regarding excitatory and inhibitory CANS function. Our goal was to measure the onset-offset N1-P2 auditory evoked response in subjects with normal hearing and subjects with moderate high-frequency sensorineural hearing loss (HFSNHL) to determine whether the response can be measured in individuals with moderate HFSNHL and, if so, whether waveform components differ between participant groups. Method Waveforms were obtained from 10 participants with normal hearing and seven participants with HFSNHL aged 40-67 years using 2,000-ms broadband noise stimuli with 40-ms rise-fall times presented at 50 dB SL referenced to stimulus threshold. Amplitudes and latencies were analyzed via repeated-measures analysis of variance (ANOVA). N1 and P2 onset latencies were compared to offset counterparts via repeated-measures ANOVA after subtracting 2,000 ms from the offset latencies to account for stimulus duration. Offset-to-onset trough-to-peak amplitude ratios between groups were compared using a one-way ANOVA. Results Responses were evoked from all participants. There were no differences between participant groups for the waveform components measured. Response × Participant Group interactions were not significant. Offset N1-P2 latencies were significantly shorter than onset counterparts after adjusting for stimulus duration (normal hearing: 43 ms shorter; HFSNHL: 47 ms shorter). Conclusions Onset-offset N1-P2 responses were resistant to moderate HFSNHL. It is likely that the onset was elicited by the presentation of a sound in silence and the offset by the change in stimulus envelope from plateau to fall, suggesting an excitatory onset response and an inhibitory-influenced offset response. Results indicated this protocol can be used to investigate CANS function in individuals with moderate HFSNHL. Supplemental Material https://doi.org/10.23641/asha.14669007.

Racial and ethnic differences in family planning telehealth use during the onset of the COVID-19 response in Arkansas, Kansas, Missouri, and Oklahoma

ObjectivesTo explore racial/ethnic disparities in family planning telehealth use. Study designWe analyzed telehealth and in-clinic visits (n = 3142) from ten family planning clinics (April 1–July 31, 2020) by race/ethnicity and month. ResultsTelehealth comprised 1257/3142 (40.0%) of overall visits. Telehealth was used by 242/765 (31.6%) of Black/African American and 31/106 (29.2%) multiracial patients. Patients with unknown (162/295, 54.9%), White (771/1870, 41.2%), and other (51/106, 48.1%) identities comprised the majority of telehealth visits. ConclusionsOur study found differences in telehealth use during the COVID-19 pandemic response. ImplicationsUnderstanding barriers and facilitators to telehealth is critical to reducing disparities in access.

Effects of Isomaltulose Ingestion on Thermoregulatory Responses during Exercise in a Hot Environment.

Isomaltulose is a low glycemic and insulinemic carbohydrate available as a constituent of sports drinks. However, it remains unclear whether thermoregulatory responses (sweating and cutaneous vasodilation) after isomaltulose drink ingestion differ from those of sucrose and water during exercise in a hot environment. Ten young healthy males consumed 10% sucrose, 10% isomaltulose, or water drinks. Thirty-five minutes after ingestion, they cycled for fifteen minutes at 75% peak oxygen uptake in a hot environment (30 °C, 40% relative humidity). Sucrose ingestion induced greater blood glucose concentration and insulin secretion at the pre-exercise state, compared with isomaltulose and/or water trials, with no differences during exercise in blood glucose. Change in plasma volume did not differ between the three trials throughout the experiment, but both sucrose and isomaltulose ingestions similarly increased plasma osmolality, as compared with water (main beverage effect, p = 0.040)—a key response that potentially delays the onset of heat loss responses. However, core temperature thresholds and slopes for heat loss responses were not different between the trials during exercise. These results suggest that ingestion of isomaltulose beverages induces low glycemic and insulinemic states before exercise but does not alter thermoregulatory responses during exercise in a hot environment, compared with sucrose or water.

Rapidity of clinical response to adalimumab and improvement of quality of life in luminal Crohn's disease: RAPIDA study

ObjectiveNo studies evaluating the rapidity of response to biological therapies are available for Crohn's disease (CD). The aim of this study was to evaluate rapidity of onset of clinical response and impact on quality of life (QoL) of adalimumab therapy in adult anti-TNF-naïve patients with moderately-to-severely active CD. Patients and methodsRAPIDA was an open-label, single-arm, prospective, multicenter clinical trial. Adult patients with moderately-to-severely active luminal CD, anti-TNF-naïve, and unresponsive to conventional therapy were treated with adalimumab. Clinical disease activity, QoL and inflammatory biomarkers were measured at day 4, and weeks 1, 2, 4, and 12 after treatment initiation. ResultsEighty-six patients were included in the intention-to-treat (ITT) analyses. Clinical disease activity was reduced from a median of 9.0 points to 6.0 points at day 4. Clinical response (≥ 3-point reduction in the Harvey-Bradshaw Index, HBI) was achieved by 61.6% (d4) and 75.6% (w1) of patients in the ITT population (median 2.5 days) and with non-responder imputation (NRI), by 55.8% and 53.4%, respectively. The proportion of patients in clinical remission (HBI<5) at weeks 2 and 4 in the ITT population was 54.7% and 62.8%, respectively (median 7.0 days), and 38.4% and 45.3% in the NRI population. All QoL scores significantly improved and inflammatory biomarkers significantly decreased from day 4 onwards (p<0.0001). ConclusionRapid clinical response and remission, improvement in QoL and fatigue, and a reduction of inflammatory biomarkers were achieved with adalimumab as early as day 4 in adult anti-TNF-naïve patients with moderately-to-severely active CD.

DOP84 Early treatment responses within 14 days of intravenous vedolizumab induction therapy for Crohn’s Disease: Post hoc analysis of patient-reported outcomes from the VISIBLE 2 study

Abstract Background Vedolizumab (VDZ), an anti-a4β7 integrin antibody that selectively blocks lymphocyte trafficking to the gut, is approved for the treatment of adult patients with moderate-to-severe Crohn’s disease (CD). This post hoc analysis of data from the VISIBLE 2 trial evaluated early patient-reported outcomes assessed within the first 14 days of VDZ induction. Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a phase 3, multicentre, placebo-controlled study, evaluating the efficacy and safety of subcutaneous VDZ for maintenance treatment in patients with moderately to severely active CD. Efficacy was assessed based on CD Activity Index (CDAI). Patients received induction treatment with intravenous (IV) VDZ 300 mg open-label at Weeks 0 and 2. For this analysis, responses to VDZ were assessed using CDAI sub-scores for patient-reported abdominal pain (AP) and stool frequency (SF) collected daily via electronic diary in the first 14 days of VDZ treatment (Day 1 to 15) in all patients receiving ≥1 VDZ dose at induction. Descriptive statistics were used. Results The analysis included 611 patients (mean [SD] age 37.6 [13.4] years; CD duration 9.0 [8.1] years); 323 (53%) were male; 228 (37%) had severe disease (CDAI &amp;gt;330) at baseline; and 350 (57%) were anti-TNF-experienced. In the first 14 days of VDZ IV induction, the rate of patients with daily SF≤3 increased from 30% at baseline (Day 1) to 47.7% on Day 15. Increases were similar in both anti-TNF-naïve vs. anti-TNF-experienced patients and in patients with severe vs. moderate disease (Figure 1). Mean baseline SF was reduced from 6.4 to 5.0 at Day 15 in patients with severe disease and from 4.3 to 3.5 in patients with moderate disease. Overall, the proportion of patients rating AP as severe/moderate declined from baseline to Day 15 of induction (from 14.6% to 8.2% for severe AP and from 60.7% to 40.6% for moderate AP). Similar Day 1-to-15 reductions were reported in both anti-TNF-naïve (severe AP: 14.2% to 9.2%; moderate AP: 62.6% to 44.6%) and anti-TNF-experienced patients (severe AP: 14.8% to 7.4%; moderate AP: 59.3% to 37.7%), respectively. Although a minority of patients (6.3%) in the sub-group with moderate AP at baseline had worse pain at Day 15, there were early improvements in AP ratings for most patients reporting severe or moderate AP at baseline (Figure 2). Conclusion This post hoc analysis of daily patient-reported SF and AP in the VISIBLE 2 CD study indicates an early onset of response to VDZ IV induction within the first 14 days of treatment.